She began her professional acting career with the Los Angeles Women's Shakespeare Company while studying at Santa Monica College, appearing in productions of The Tempest and Romeo and Juliet.

Thompson gained favorable notices for roles in the comedy-drama Dear White People (2014), and as civil rights activist Diane Nash in Ava DuVernay's historical drama Selma (2014).

[6] Thompson made her first television appearance in a 2005 episode of the CBS crime drama series Cold Case in the role of a lesbian bootlegger from the 1930s.

That same year, Thompson played civil rights activist Diane Nash in Ava DuVernay's Martin Luther King Jr. biopic Selma.

[11] In 2016, she began a starring role in the HBO science fiction drama series Westworld as board director Charlotte Hale.

[12][13] Also in 2016, Thompson appeared in the off-Broadway run of the Lydia R. Diamond play Smart People at Second Stage Theatre, starring alongside Mahershala Ali, Joshua Jackson and Anne Son.

[19] She reprised her role as Bianca Taylor in the sports drama sequel film Creed II, which was released on November 21, 2018, to positive reviews and strong box office returns.

[citation needed] At the 2019 San Diego Comic-Con, it was announced that Thompson would reprise her role as King Valkyrie "Val" in the superhero film Thor: Love and Thunder (2022), as a part of Phase Four of the Marvel Cinematic Universe.

[25] In January 2021, it was reported that her production company had signed a first look deal at HBO and would executive produce adaptations of two novels, Who Fears Death and The Secret Lives of Church Ladies.

[31][32] Thompson made her directorial debut with the music video for "Raat Ki Rani", the lead single of Arooj Aftab's 2024 album Night Reign.